Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of thereof

Abstract

The invention relates generally to antibodies that bind programmed death ligand 1 (PDL1), activatable antibodies that specifically bind to PDL1 and methods of making and using these anti-PDL1 antibodies and anti-PDL1 activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.

What is claimed: 
     
       1. An isolated antibody or antigen binding fragment thereof (AB) wherein the AB comprises:
 (a) a heavy chain variable region (VH) comprising:
 i. a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 2.12; 
 ii. a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 246; 
 iii. a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO: 235; and 
 
 (b) a light chain variable region (VL) comprising:
 i. a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 209; 
 ii. a variable light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence of SEQ ID NOs: 215 or 227; and 
 iii. a variable light chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of SEQ ID NO: 228, 
 
 wherein the AB specifically binds mammalian PDL1. 
 
     
     
       2. A conjugated antibody comprising the antibody of  claim 1  conjugated to an agent. 
     
     
       3. The antibody of  claim 1 , wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 215. 
     
     
       4. A pharmaceutical composition comprising the antibody of  claim 1  and a carrier. 
     
     
       5. A pharmaceutical composition comprising the conjugated antibody of  claim 2  and a carrier. 
     
     
       6. An activatable antibody comprising the following structure:
 (1) an antibody or an antigen binding fragment thereof (AB) that specifically binds to mammalian PDL1, wherein the AB comprises:
 (a) a variable heavy chain region (VH) comprising:
 i. a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 212; 
 ii. a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 246; and 
 iii. a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO:235; and 
 
 (b) a variable light chain region (VL) comprising:
 i. a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 209; 
 ii. a variable light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence of SEQ ID NOs: 215 or 227; and 
 iii. a variable light chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of SEQ ID NO: 228; 
 
 
 (2) a masking moiety (MM) comprising the amino acid sequence of SEQ ID NO: 63; and 
 (3) a cleavable moiety (CM) comprising the amino acid sequence of SEQ ID NO: 377. 
 
     
     
       7. The activatable antibody of  claim 6 , wherein the AB is linked to the CM. 
     
     
       8. The activatable antibody of  claim 7 , wherein the AB is linked directly to the CM. 
     
     
       9. The activatable antibody of  claim 7 , wherein the AB is linked to the CM via a linking peptide. 
     
     
       10. The activatable antibody of  claim 6 , wherein the MM is linked to the CM such that the activatable antibody in an uncleaved state comprises the structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM. 
     
     
       11. The activatable antibody of  claim 10 , wherein the activatable antibody comprises a linking peptide between the MM and the CM, a linking peptide between the CM and the AB, or both a linking peptide between the MM and the CM and a linking peptide between the CM and the AB. 
     
     
       12. The activatable antibody of  claim 10 , wherein the activatable antibody comprises a first linking peptide (LP1) and a second linking peptide (LP2), and wherein the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM. 
     
     
       13. The activatable antibody of  claim 12 , wherein the two linking peptides need not be identical to each other. 
     
     
       14. The activatable antibody of  claim 12 , wherein each of LP1 and LP2 is a peptide of about 1 to 20 amino acids in length. 
     
     
       15. A conjugated activatable antibody comprising the activatable antibody of  claim 6  conjugated to an agent. 
     
     
       16. The conjugated activatable antibody of  claim 15 , wherein the agent has one or more of the following characteristics selected from the group consisting of:
 (i) the agent is a toxin or fragment thereof; 
 (ii) the agent is a microtubule inhibitor; 
 (iii) the agent is a nucleic acid damaging agent; 
 (iv) the agent is a dolastatin or a derivative thereof; 
 (v) the agent is an auristatin or a derivative thereof; 
 (vi) the agent is a maytansinoid or a derivative thereof; 
 (vii) the agent is a duocarmycin or a derivative thereof; 
 (viii) the agent is a calicheamicin or a derivative thereof; 
 (ix) the agent is auristatin E or a derivative thereof; 
 (x) the agent is monomethyl auristatin E (MMAE); 
 (xi) the agent is monomethyl auristatin D (MMAD); 
 (xii) the agent is DM1; 
 (xiii) the agent is DM4; 
 (xiv) the agent is a detectable moiety; 
 (xv) the agent is a diagnostic agent; 
 (xvi) the agent is conjugated to the antibody via a linker; 
 (xvii) the agent is conjugated to the antibody via a cleavable linker; and 
 (xviii) the agent is conjugated to the antibody via a non-cleavable linker. 
 
     
     
       17. A pharmaceutical composition comprising the activatable antibody of  claim 6  and a carrier. 
     
     
       18. The pharmaceutical composition of  claim 17  comprising an additional agent. 
     
     
       19. The pharmaceutical composition of  claim 18 , wherein the additional agent is a therapeutic agent. 
     
     
       20. The activatable antibody of  claim 6 , wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 215. 
     
     
       21. The activatable antibody of  claim 6 , wherein the AB comprises a VH comprising the amino acid sequence of SEQ ID NO: 46 and a VL comprising the amino acid sequence of SEQ ID NO: 12. 
     
     
       22. The activatable antibody of  claim 6 , wherein the AB comprises a VH comprising the amino acid sequence of SEQ ID NO: 46 and a VL comprising the amino acid sequence of SEQ ID NO: 58. 
     
     
       23. The activatable antibody of  claim 6 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 137 and a VH comprising the amino acid sequence of SEQ ID NO: 46. 
     
     
       24. The activatable antibody of  claim 6 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 985 and a VH comprising the amino acid sequence of SEQ ID NO: 46. 
     
     
       25. The activatable antibody of  claim 6 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 428 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 432. 
     
     
       26. The activatable antibody of  claim 6 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1008 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 432. 
     
     
       27. The pharmaceutical composition comprising the antibody of  claim 3  and a carrier. 
     
     
       28. The pharmaceutical composition comprising the activatable antibody of  claim 20  and a carrier. 
     
     
       29. A pharmaceutical composition comprising the activatable antibody of  claim 25  and a carrier. 
     
     
       30. The pharmaceutical composition of  claim 29  comprising an additional agent. 
     
     
       31. A pharmaceutical composition comprising the activatable antibody of  claim 26  and a carrier. 
     
     
       32. A pharmaceutical composition comprising the activatable antibody of  claim 24  and a carrier. 
     
     
       33. A pharmaceutical composition comprising the activatable antibody of  claim 26  and a carrier. 
     
     
       34. A pharmaceutical composition comprising the conjugated activatable antibody of  claim 15  and a carrier. 
     
     
       35. A method of reducing PDL1 activity comprising administering an effective amount of the antibody of  claim 1  to a subject in need thereof. 
     
     
       36. A method of blocking binding of a natural ligand to PDL1 comprising administering an effective amount of the antibody of  claim 1  to a subject in need thereof. 
     
     
       37. A method of treating, alleviating a symptom of, or delaying the progression of a PDL1-mediated disorder or disease comprising administering an effective amount of the antibody of  claim 1  to a subject in need thereof. 
     
     
       38. A method of reducing PDL1 activity comprising administering an effective amount of the activatable antibody of  claim 6  to a subject in need thereof. 
     
     
       39. A method of blocking binding of a natural ligand to PDL1 comprising administering an effective amount of the activatable antibody of  claim 6  to a subject in need thereof. 
     
     
       40. A method of treating, alleviating a symptom of, or delaying the progression of a PDL1-mediated disorder or disease comprising administering a therapeutically effective amount of the activatable antibody of  claim 6  to a subject in need thereof. 
     
     
       41. The method of  claim 40 , wherein the PDL1-mediated disorder or disease is cancer. 
     
     
       42. The method of  claim 41 , wherein the cancer is a bladder cancer, a bone cancer, a breast cancer, a carcinoid, a cervical cancer, a colon cancer, an endometrial cancer, a glioma, a head and neck cancer, a liver cancer, a lung cancer, a lymphoma, a melanoma, an ovarian cancer, a pancreatic cancer, a prostate cancer, a renal cancer, a sarcoma, a skin cancer, a stomach cancer, a testis cancer, a thyroid cancer, a urogenital cancer, or a urothelial cancer. 
     
     
       43. The method of  claim 41 , wherein the cancer is selected from the group consisting of melanoma (MEL), renal cell carcinoma (RCC), squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer (CRC), castration-resistant prostate cancer (CRPC), hepatocellular carcinoma (HCC), squamous cell carcinoma of the head and neck, carcinomas of the esophagus, ovary, gastrointestinal tract and breast, or a hematologic malignancy such as multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. 
     
     
       44. The method of  claim 40 , wherein the method comprises administering an additional agent. 
     
     
       45. The method of  claim 44 , wherein the additional agent is a therapeutic agent. 
     
     
       46. The method of  claim 40 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 428 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 432, and wherein the PDL1-mediated disorder or disease is cancer. 
     
     
       47. The method of  claim 40 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1008 and aheavy chain comprising the amino acid sequence of SEQ ID NO: 432, and wherein the PDL1-mediated disorder or disease is cancer. 
     
     
       48. The method of  claim 40 , wherein the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 985 and a VH comprising the amino acid sequence of SEQ ID NO: 46, and wherein the PDL1-mediated disorder or disease is cancer.